EP2651891B1 - Phénols à fonctionnalité amide substitués par un système cyclique bicyclique en tant que médicaments - Google Patents

Phénols à fonctionnalité amide substitués par un système cyclique bicyclique en tant que médicaments Download PDF

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EP2651891B1
EP2651891B1 EP11801712.8A EP11801712A EP2651891B1 EP 2651891 B1 EP2651891 B1 EP 2651891B1 EP 11801712 A EP11801712 A EP 11801712A EP 2651891 B1 EP2651891 B1 EP 2651891B1
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compound
mmol
phenyl
alkyl
amino
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EP2651891A1 (fr
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Riccardo Giovannini
Dieter Hamprecht
Barbara Kistler
Iain Lingard
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Boehringer Ingelheim International GmbH
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to bicyclic ring system substituted amide functionalized phenols and their use as inhibitors of CXCR2 activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin, or eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions which contain these compounds.
  • Cellular movement and placement represents a fundamental property of cells of the immune system. It enables their mobilization and expansion to sites of pathogen challenge. Cell movement is also essential for the complex T cell, B cell and dendritic cell interactions to orchestrate the immune response. For cell migration chemoattractants that signal through seven-transmembrane-G-protein-coupled receptors are of central importance.
  • chemoattractant cytokines chemokines
  • T and B lymphocytes including T and B lymphocytes, natural killer (NK) cells, neutrophils, eosinophils, basophils, dendritic cells (DC) and nonleukocytic cells, such as endothelial cells, fibroblasts, smooth muscle cells, are able to respond to chemotactic stimuli.
  • NK natural killer
  • DC dendritic cells
  • nonleukocytic cells such as endothelial cells, fibroblasts, smooth muscle cells
  • Chemokines have been classified into 4 subfamilies based on the presence of cysteines at the N-terminal part of the protein. CXC, CC, CX3C and C. CXC chemokines can be further subclassified into Glutamin-Leucin-Arginine containing (ELR+) and ELR- chemokines (not containing this tripeptide motif). All members of the ELR+ family of chemokines (CXCL1-3 and CXCL5-8) bind to and activate the CXC chemokines receptor 2 (CXCR2), two members (CXCL6 and 8) additionally bind and activate CXCR1. CXCR2 is expressed in the myeloid compartment (e.g. neutrophils, monocytes). It has attracted particular attention, as it has been shown to play a crucial role in the development and promotion of numerous inflammatory diseases and tumor progression.
  • the present invention describes low molecular weight bicyclic ring system substituted amide functionalized phenols with CXCR2 antagonist activity. It has been surprisingly found that the compounds of the present invention have a superior efficacy in inhibition of CXCR2 dependent chemotaxis. In addition, compounds of the present invention have been found to have satisfactory pharmacokinetic properties.
  • radical attachment point(s) to the molecule from the free valences of the group itself.
  • the last named subgroup is the radical attachment point, for example, the substituent "aryl-C 1-3 -alkyl-" means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • 3-carboxypropyl-group represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group.
  • the terms "1-methylpropyl-", “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc%) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,
  • salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19 ).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts, also comprise a part of the invention.
  • halogen generally denotes fluorine, chlorine, bromine and iodine.
  • C 1-n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • C 1-5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3
  • Carbocyclyl as used either alone or in combination with another radical, means a mono- bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms.
  • the term “carbocycle” refers to fully saturated and aromatic ring systems and partially saturated ring systems.
  • the term “carbocycle” encompasses fused, bridged and spirocyclic systems.
  • C 3-n -cycloalkyl wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
  • heterocycle is intended to include all the possible isomeric forms.
  • heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • heteroaryl is intended to include all the possible isomeric forms.
  • heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • R 1 is phenyl or furanyl, optionally substituted by one or two residues selected from halogen or C 1-6 -alkyl, optionally substituted with one or more F atoms.
  • 3-Nitrosalicylic acid protected with protecting group P where necessary, is activated with a suitable reagent and coupled with a bicyclic amine to give intermediate A .
  • the nitro group is reduced under suitable conditions to give intermediate B which is reacted with an isocyanate or equivalent reagent to give intermediate C .
  • Protecting groups (if used) are then removed to give the required product as shown in the general Scheme 1 below.
  • 3-aminosalicylic acid protected with protecting group P where necessary, is reacted with an isocyanate or equivalent reagent to give intermediate E, which is activated with a suitable reagent and coupled with a bicyclic amine to give intermediate C.
  • Protecting groups are then removed to give the required product as shown in the general Scheme 3 below.
  • 3-aminosalicylic acid protected with protecting group P where necessary, is reacted with 3,4-diethoxy-3-cyclobutene-1,2-dione or a similar reagent to give intermediate I, which is reacted with a suitable amine to give intermediate J.
  • This is activated with a suitable reagent and coupled with a bicyclic amine to give intermediate H.
  • Protecting groups (if used) are then removed to give the required product as shown in the general Scheme 6 below.
  • Suitable protecting groups P for the syntheses described above and suitable conditions for their use can be chosen by those skilled in the art from examples described in " Protecting Groups, 3rd Edition", Philip J. Kocienski, Theime, 2005 or " Greene's Protective Groups in Organic Synthesis, 4th Edition", Peter G. M. Wuts, Theodora W. Greene, John Wiley and Sons, 2007 .
  • GC/MS were performed under the following conditions: GC/MS Method 7 Instrument: GC/MS Thermo Scientific TRACE GC ULTRA, DSQ II MS single quadrupole Column: Agilent DB-5MS, 25m x 0.25mm x 0.25 ⁇ m Carrier gas: Helium, 1 ml/min constant flow Oven Program: 50 °C, to 100 °C in 10 °C/min, to 200 °C in 20 °C/min, to 320 °C in 30 °C/min (hold 10 min). Detection: DSQ II MS single quadrupole Ion source: EI Scan range: 50- 450 amu
  • Flash chromatography is performed on prepacked silica gel columns from Biotage using FlashVac (IST), Flashmaster (Argonaut) SP1 or Isolera (Biotage) manual and automatic purification systems.
  • SCX columns are purchased from Biotage or Phenomenex and are washed with methanol prior to use.
  • Reactions are monitored by TLC using suitable solvents and visualisation by UV absorbance or a suitable staining reagent.
  • Example Structure Analysis 2 ES mass spectrum: [M+H] + 477 Retention time: 7.50 min (HPLC Method 5) 1 H NMR (Varian Inova 500 MHz. DMSO-d6; 27 °C) 9.11 (1H, br); 8.79 (1H, br); 7.91 (1H, dd); 7.83 (1H, d); 7.63 (3H, m); 7.29 (1H, t); 6.83 (2H, m); 3.90 (2H, br); 3.12 (4H, m); 1.98 (2H, t); 1.64 (2H, m); 1.38 (2H, m); 1 H not observed.
  • Example 8-2 is treated in a manner analogous to that described for Example 1.
  • the product is isolated by flash chromatography (Silica Gel, gradient: dichloromethane/methanol from 100:0 to 90:10) to give Example 8.
  • Yield: 40 mg ES mass spectrum: [M+H] + 459 Retention time: 6.58 (HPLC Method 6) 1 H NMR (Varian Inova 500 MHz.
  • Compound 10-2 is prepared from compound 10-1 in a manner analogous to that described for compound 1-2.
  • Example 10-2 is treated in a manner analogous to that described for Example 1.
  • Compound 10-2 is treated in a manner analogous to that described for compound 9-1.
  • Example 12 The following compounds are prepared from compound 12-2 in a manner analogous to that described for the preparation of Example 1 with the appropriate isocyanate ( Examples 12 and 13 ), or in a manner analogous to that described for the preparation of Example 9 ( Example 14 ).
  • Example Structure Analysis 12 ES mass spectrum: [M+H] + 473 Retention time: 9.72 min (HPLC Method 6) 1 H NMR (Varian Inova 500 MHz.
  • 4-Nitrophenylchloroformate (663 mg, 3.29 mmol) is dissolved in dry dichloromethane (10 mL) and cooled to 0 °C.
  • a solution of 2-chloro-3-fluoroaniline (479 mg, 3.29 mmol) and pyridine (355 ⁇ L 4.48 mmol) in dry DCM (10 mL) is added dropwise and the mixture stirred for 15 minutes at 0°C then 1h at room temperature.
  • 3-Amino-2-methoxybenzoic acid 500 mg, 2.99 mmol
  • pyridine (710 ⁇ L, 9 mmol) in DCM (10 mL) are added and the mixture stirred for 2 hours.
  • Compound 17-5 (150 mg, 0.96 mmol) is suspended in dry THF (5 mL) and borane THF complex (1M in THF, 9.6 mL, 9.6 mmol) added. The mixture is heated at 90 °C for 28 hours. The mixture is loaded onto a 10 g SCX cartridge, washed with methanol and then eluted with 2 M ammonia solution in methanol. The solvent is removed under reduced pressure, the residue cooled in an ice bath and hydrogen chloride (6 M in dioxane, 10 mL) added. The mixture is heated at 60 °C for 4 hours and the solvent removed.
  • Chemotaxis assay 1 transfected cell line: This assay measures the inhibition of CXCL1 induced chemotaxis of BAF/3 cells expressing human CXCR2. For each assay point, 100 ⁇ L of a 3 x 10 6 /mL cell suspension are incubated with 1 ⁇ L of test compound diluted in DMSO. The bottom wells of a chemotaxis plate (5 ⁇ m pore size, Neuroprobe) is filled with 305 ⁇ L of chemotaxis buffer (RPMI 1640 medium (phenol red free), containing 2 % fetal calf serum) and 3 nM CXCL1.
  • RPMI 1640 medium phenol red free
  • the 5 ⁇ m pore membrane is applied onto the chemotaxis plate and 80 ⁇ L of the cell suspension is cautiously pipetted onto the membrane.
  • the lid is put on the chemotaxis plate and the plate is incubated for 4 hours in an incubator (37 °C, 5% CO2).
  • the cell suspension and the lid are removed and 100 ⁇ L from the bottom chamber are transferred to an Opti plate 96 (Perkin Elmer).
  • 100 ⁇ L of substrate solution (provided by Cell Titer Glo kit, Promega) are added. This method uses the measurement of ATP present in metabolically active cells. After 10 min incubation at room temperature the plate is measured at Luminoscan for quantification of ATP-dependent generation of oxyluciferin.
  • IC50s of the tested compound are calculated by non-linear regression and using a sigmoidal dose-response curve as fitting algorithm (provided by GraphPadPrism). Determination of a bottom value is performed by quantification of migration of buffer treated cells, migrating towards buffer only. Determination of a top value is performed by quantification of migration of buffer treated cells, migrating towards CXCL1.
  • Chemotaxis assay 2 primary human PMN (polymorph nuclear cells) from healthy donors: This assay measures the inhibition of CXCL1 induced chemotaxis of primary human PMN cells isolated from healthy donors. Neutrophils, the major type of human PMN cells express both CXCR1 and CXCR2. CXCL1 specifically binds to CXCR2, not CXCR1 and therefore, upon stimulation with CXCL1 measurements are focused on CXCR2.
  • human whole blood is mixed with DPBS and ACD buffer (38 mM citric acid, 75 mM tri-sodium citrate, 121 mM glucose) to prevent coagulation. Blood, DPBS and ACD buffer are mixed at a ratio of 4:1:1.
  • the anti-coagulated blood is layered over 18-20 mL Ficoll (Ficoll-Paqu TM Plus) and centrifuged for 30 min at 300 x g, without brake. Supernatant containing mononuclear cells is discarded. Pellet contains PMN cells and erythrocytes. For lysis of erythrocytes, the pellet is suspended with 30 mL of ammonium hydroxide buffer (155 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA, pH 5.0) and incubated for 8 minutes on ice.
  • ammonium hydroxide buffer 155 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA, pH 5.0
  • a 5 ⁇ m pore chemotaxis plate (Neuro-Probe) are filled with either 305 ⁇ L HBSS buffer (negative control) of HBSS buffer containing 10 nM CXCL1.
  • the membrane is applied onto the chemotaxis plate and 80 ⁇ l of the cell suspension is cautiously pipetted onto the membrane.
  • the lid is put on the chemotaxis plate and the plate is incubated for 1 hour in an incubator (37 °C, 5 % CO2).
  • the cell suspension and the lid are removed and 100 ⁇ l from the bottom chamber are transferred to an Opti plate 96 (Perkin Elmer). 100 ⁇ l of substrate solution (provided by Cell Titer Glo kit, Promega) are added.
  • IC50s of the tested compound are calculated by non-linear regression and using a sigmoidal dose-response curve as fitting algorithm (provided by GraphPadPrism). Determination of a bottom value was performed by quantification of migration of buffer treated cells, migrating towards buffer only. Determination of a top value was performed by quantification of migration of buffer treated cells, migrating towards CXCL1.
  • the compounds of formula 1 may be used on their own or in conjunction with other active substances of formula 1 according to the invention. If desired the compounds of formula 1 may also be used in combination with other pharmacologically active substances. It is preferable to use for this purpose active substances selected for example from among ß2-adrenoceptor-agonists (short and lon-acting betamimetics), anti-cholinergics (short and lon-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, statins, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine
  • the compounds of formula 1 may be used on their own or in conjunction with other active substances of formula I according to the invention. If desired the compounds of formula I may also be used in combination with other pharmacologically active substances. It is preferable to use for this purpose active substances selected for example from among ß2-adrenoceptor-agonists (short and lon-acting betamimetics), anti-cholinergics (short and lon-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, statins, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine
  • betamimetics examples include Albuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and
  • Examples of preferred anticholinergics which may be mentioned include Tiotropium salts, preferred the bromide salt, Oxitropium salts, preferred the bromide salt, Flutropium salts, preferred the bromide salt, Ipratropium salts, preferred the bromide salt, Aclidinium salts, preferred the bromide salt, Glycopyrronium salts, preferred the bromide salt, Trospium salts, preferred the chloride salt, Tolterodin.
  • the pharmacologically active part is the cation
  • possible anions are chloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate.
  • preferred anticholinergics are selected from among
  • corticosteroids examples include Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, Etiprednole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofleponide, Triamcinolone, Tepredane, and
  • PDE4-inhibtors examples include Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste , Pumafentrine , Lirimilaste , Apremilaste, Arofylline, Atizorame, Oglemilastum, Tetomilaste and
  • salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
  • EGFR-inhibitors examples include Cetuximab, Trastuzumab, Panitumumab Gefitinib, Canertinib, Erlotinib, Mab ICR-62 and
  • Examples of preferred antiallergic agents include Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebastine, Olopatadine, Desloratidine and Meclozine, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
  • salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
  • MAP kinase inhibitors examples include
  • the present invention is directed to compounds of general formula 1 which are useful in the prevention and/or treatment of a disease and/or condition wherein the activity of CXCR2 antagonism is of therapeutic benefit, including but not limited to the treatment and/or prevention of inflammatory diseases.
  • inflammatory diseases include respiratory or gastrointestinal diseases or complaints, inflammatory diseases of the joints, skin, or eyes, cancers and also diseases of the peripheral or central nervous system.
  • the compounds of general formula 1 are useful for the prevention and/or treatment of diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations, and/or obstructive diseases of the airways.
  • diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations, and/or obstructive diseases of the airways.
  • Examples include acute, allergic, or chronic bronchitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyper-reactive airways, infections, bronchitis, pneumonitis, paediatric asthma, bronchiectases, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchitis, pneumonia or intersti
  • the present invention relates to the use of a compound of general formula 1 for the treatment and/or prevention of a disease and/or condition wherein the activity of CXCR2 antagonism is of therapeutic benefit.
  • the present invention relates to the use of a compound of general formula 1 for the treatment and/or prevention of inflammatory diseases.
  • inflammatory diseases examples include respiratory or gastrointestinal diseases or complaints, inflammatory diseases of the joints, skin, or eyes, cancers and also diseases of the peripheral or central nervous system.
  • the present invention relates to the use of a compound of general formula 1 for the treatment and/or prevention of diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations, and/or obstructive diseases of the airways.
  • diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations, and/or obstructive diseases of the airways.
  • Examples include acute, allergic, or chronic bronchitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyper-reactive airways, infections bronchitis or pneumonitis, paediatric asthma, bronchiectases, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchi
  • the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula 1 to a human being.
  • the dose range of the compounds of general formula 1 applicable per day is usually from 0.1 mg to 500 mg, preferably from 1 mg to 50 mg.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • the preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension.
  • a tablet e.g. a powder
  • a capsule e.g. a hard gelatine capsule
  • the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
  • pharmaceutical formulations are characterised in that they contain one or more compounds of formula I according to the preferred embodiments above.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets may also comprise several layers.
  • Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core may also consist of a number of layers.
  • the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p -hydroxybenzoates.
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g.
  • pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
  • lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
  • the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
  • the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
  • the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day.
  • the compounds of formula I have to be made available in forms suitable for inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
  • propellant-free inhalable solutions also include concentrates or sterile ready-to-use inhalable solutions.
  • the preparations which may be used according to the invention are described in more detail in the next part of the specification.
  • physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, saccharose, maltose
  • oligo- and polysaccharides e.g. dextran
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
  • the propellant-containing inhalable aerosols which may be used according to the invention may contain 1 dissolved in the propellant gas or in dispersed form.
  • the propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the propellant gases mentioned above may be used on their own or in mixtures thereof.
  • propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-driven inhalation aerosols used within the scope of the use according to the invention may also contain other ingredients such as co--solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
  • the compounds of formula I according to the invention are preferably used to prepare propellant-free inhalable solutions and inhalable suspensions.
  • Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions.
  • the solvent may be water on its own or a mixture of water and ethanol.
  • the solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.
  • the pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
  • organic acids examples include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc.
  • Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances.
  • ascorbic acid, fumaric acid and citric acid are preferred.
  • mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example.
  • hydrochloric acid it is particularly preferred to use hydrochloric acid to adjust the pH.
  • Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect.
  • the excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body.
  • Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from those described above.

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Claims (11)

  1. Composé de formule 1,
    Figure imgb0273
     dans laquelle
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi un halogène ou un C1-4 alkyle, facultativement substitué avec un ou plusieurs atomes F ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0274
    R3 est H, un halogène, CN, un C1-4 alkyle, facultativement substitué avec F ;
    A est un système hétérocyclique bicyclique de formule
    Figure imgb0275
    Figure imgb0276
     où
    • s'il est présent, un groupe CH est facultativement remplacé par N ; et
    • un, deux ou trois groupes CH2 sont facultativement remplacés par un C1-6 alkyl-CH-, un (C1-6 alkyl)2-C-, un C1-6 alkyl-OC(O)CH-, CO, O, NH, un (C1-6 alkyl)N-, SO2, dans lequel les groupes C1-6, alkyle sont facultativement substitués avec OH
    ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé de formule 1 selon la revendication 1, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0277
    R3 est H, Cl, CN, CF3 ;
    A est un système hétérocyclique bicyclique de formule
    Figure imgb0278
    Figure imgb0279
     où
    • s'il est présent, un groupe CH est facultativement remplacé par N ; et
    • un, deux ou trois groupes CH2 sont facultativement remplacés par CHMe, CMe2, CHCH2OH, CHCOOMe, CO, O, NH, NMe, SO2
    ou un sel pharmaceutiquement acceptable de celui-ci.
  3. Composé de formule 1 selon l'une quelconque des revendications 1 à 2, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0280
    R3 est H, Cl, CN, CF3 ;
    A est un système hétérocyclique bicyclique sélectionné dans le groupe consistant en
    Figure imgb0281
    Figure imgb0282
    Figure imgb0283
    Figure imgb0284
    Figure imgb0285
    Figure imgb0286
     ou un sel pharmaceutiquement acceptable de celui-ci.
  4. Composé de formule 1 selon l'une quelconque des revendications 1 à 3, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0287
    R3 est H, Cl, CN, CF3 ;
    A est un système hétérocyclique bicyclique de formule
    Figure imgb0288
    Figure imgb0289
     où
    • s'il est présent, un groupe CH est facultativement remplacé par N ; et
    • un, deux ou trois groupes CH2 sont facultativement remplacés par CHMe, CMe2, CHCH2OH, CHCOOMe, CO, O, NH, NMe,
    ou un sel pharmaceutiquement acceptable de celui-ci.
  5. Composé de formule 1 selon l'une quelconque des revendications 1 à 3, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0290
    R3 est H ;
    A est un système hétérocyclique bicyclique sélectionné dans le groupe consistant en
    Figure imgb0291
    Figure imgb0292
    Figure imgb0293
    Figure imgb0294
     ou un sel pharmaceutiquement acceptable de celui-ci.
  6. Composé de formule 1 selon l'une quelconque des revendications 1 à 3, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0295
    R3 est H, Cl, CN, CF3 ;
    A est un système hétérocyclique bicyclique de formule
    Figure imgb0296
     où
    • un groupe CH est facultativement remplacé par N ; et
    • un, deux ou trois groupes CH2 sont facultativement remplacés par CHMe, CMe2, CO, O, NH, NMe,
    ou un sel pharmaceutiquement acceptable de celui-ci.
  7. Composé de formule 1 selon l'une quelconque des revendications 1 à 3, dans lequel
    R1 est sélectionné dans le groupe consistant en un phényle, un furanyle, facultativement substitué avec un ou deux résidus sélectionnés parmi Me, CF3, F, Cl ;
    X1 est absent ou est un C1-4 alkyle ramifié ou non ramifié ; ledit alkyle étant facultativement substitué avec un ou plusieurs atomes F ;
    R2 est H ;
    X2 est
    Figure imgb0297
    R3 est H ;
    A est un système hétérocyclique bicyclique sélectionné dans le groupe consistant en
    Figure imgb0298
    Figure imgb0299
     ou un sel pharmaceutiquement acceptable de celui-ci.
  8. Composé de formule 1 selon l'une quelconque des revendications 1 à 7 ou sel pharmaceutiquement acceptable de celui-ci, pour son utilisation comme médicament.
  9. Composé de formule 1 selon l'une quelconque des revendications 1 à 7 ou sel pharmaceutiquement acceptable de celui-ci, pour son utilisation dans le traitement et/ou la prévention des maladies des voies respiratoires et des poumons qui s'accompagnent d'une augmentation de la production de mucus, des inflammations et/ou des maladies obstructives des voies respiratoires ; ou des affections ou maladies gastrointestinales, des maladies inflammatoires des articulations, de la peau ou des yeux, des maladies du système nerveux central ou périphérique ou des cancers, ainsi que les compositions pharmaceutiques qui contiennent ces composés.
  10. Composé de formule 1 selon l'une quelconque des revendications 1 à 7 ou sel pharmaceutiquement acceptable de celui-ci, pour son utilisation dans le traitement et/ou la prévention d'une bronchite aiguë, allergique ou chronique, d'une bronchite chronique obstructive (MPCO), de la toux, d'un emphysème pulmonaire, d'une rhinite ou sinusite allergique ou non allergique, d'une rhinite ou sinusite chronique, de l'asthme, d'une alvéolite, de la maladie du fermier, des voies respiratoires hyper-réactives, des infections, d'une bronchite, d'une pneumonite, de l'asthme pédiatrique, d'une bronchectasie, d'une fibrose pulmonaire, du SRDA (syndrome de détresse respiratoire aiguë de l'adulte), d'un oedème bronchique, d'un oedème pulmonaire, d'une bronchite, pneumonie ou pneumonie interstitielle déclenchée par diverses causes, comme l'aspiration, l'inhalation de gaz toxiques, ou d'une bronchite, pneumonie ou pneumonie interstitielle résultant d'une insuffisance cardiaque, d'une irradiation, d'une chimiothérapie, d'une fibrose kystique ou d'une mucoviscidose, ou d'une déficience en alpha-1 antitrypsine.
  11. Composition pharmaceutique contenant au moins un composé de formule 1 selon l'une quelconque des revendications 1 à 10 ou un sel pharmaceutiquement acceptable de celui-ci, conjointement avec un ou plusieurs supports pharmaceutiquement acceptables.
EP11801712.8A 2010-12-17 2011-12-16 Phénols à fonctionnalité amide substitués par un système cyclique bicyclique en tant que médicaments Active EP2651891B1 (fr)

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EP10195639 2010-12-17
PCT/EP2011/073025 WO2012080456A1 (fr) 2010-12-17 2011-12-16 Phénols à fonctionnalité amide substitués par un système cyclique bicyclique en tant que médicaments
EP11801712.8A EP2651891B1 (fr) 2010-12-17 2011-12-16 Phénols à fonctionnalité amide substitués par un système cyclique bicyclique en tant que médicaments

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EP2651891A1 (fr) 2013-10-23

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